Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

Background JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced...

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Published in:Cancer Immunology, Immunotherapy : CII Immunotherapy : CII, 2024-08, Vol.73 (10), p.205, Article 205
Main Authors: Geva, Ravit, Vieito, Maria, Ramon, Jorge, Perets, Ruth, Pedregal, Manuel, Corral, Elena, Doger, Bernard, Calvo, Emiliano, Bardina, Jorge, Garralda, Elena, Brown, Regina J., Greger, James G., Wu, Shujian, Steinbach, Douglas, Yao, Tsun-Wen Sheena, Cao, Yu, Lauring, Josh, Chaudhary, Ruchi, Patel, Jaymala, Patel, Bharvin, Moreno, Victor
Format: Article
Language:English
Subjects:
Antigens
Antitumor activity
Bispecific antibodies
Cancer Research
CD3 antigen
Cell activation
Colorectal carcinoma
Cytokines
Dosage
Histocompatibility antigen HLA
Immunohistochemistry
Immunology
Leukocytes
Lymphocytes T
Medicine
Medicine & Public Health
Metastases
NCT
NCT04991740
Oncology
Ovarian cancer
Ovarian carcinoma
Patients
Pharmacodynamics
Pharmacokinetics
Pneumonitis
Renal cell carcinoma
Solid tumors
Tumor cells
Tumors
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Summary:Background JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors. Methods Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS). Results Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry. Conclusion JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).
ISSN:1432-0851
0340-7004
1432-0851
DOI:10.1007/s00262-024-03790-7